The goal of the proposed research is to use a chemical biology approach to elucidate novel molecular mechanisms involved in the regulation of the Wnt/GSK3/beta-catenin signaling pathway, which is implicated in the pathophysiology and treatment of bipolar disorder. Recent work by the candidate showed that histone deacetylases (HDACs) play a role in modulation of beta-catenin levels. The candidate hypothesizes that specific histone deacetylase isoforms regulate beta-catenin levels and that elucidation of the mechanism(s) underlying HDAC regulation of beta-catenin levels will lead to a fundamental understanding of the Wnt signaling pathway and the identification of novel therapeutic targets for bipolar disorder. The research proposal aims to identify the specific HDAC isoforms that regulate beta-catenin levels, using RNAi against specific HDAC isoforms as well as novel isoform-specific HDAC inhibitors. The proposal aims to characterize mechanism(s) underlying HDAC modulation of beta-catenin signaling, by examining effects on chromatin remodeling as well as acetylation of lysine residues on beta-catenin itself. A systematic study of the lysine acetylation and the GSK-3 and casein kinase-1 (CK1) phosphorylation sites on beta-catenin will be conducted to delineate the temporal and regulatory effects of the phosphorylation and acetylation events. The proposal further aims to study the effects of beta-catenin modulating HDAC inhibitors on the proliferation and differentiation of human neural progenitor cells. The candidate is a physician-scientist with clinical training in psychiatry, with a focus on schizophrenia and bipolar disorder. He is currently conducting post-doctoral research in chemical biology, focusing on discovery of novel mechanisms that regulate beta-catenin signaling. His long-term goal is to establish and direct an academic research laboratory applying novel strategies in chemical biology to clinically-relevant challenges in bipolar disorder and schizophrenia. The proposed research will be carried out under the sponsorship of two mentors: Dr. Stuart L. Schreiber in the Chemical Biology Program at the Broad Institute of Harvard and MIT and Dr. Bruce M. Cohen in McLean Hospital. This award will support a unique training experience in clinically-informed research in chemical biology, and will establish an academic pathway for the discovery and development of experimental therapeutics for bipolar disorder and schizophrenia. PUBLIC HEALTH RELEVANCE: The development of improved therapeutics for bipolar disorder remains a significant unmet medical need. Identification of small molecules that regulate the Wnt-GSK-3/beta-catenin pathway through novel mechanims could lead to the development of alternative therapeutic agents with greater efficacy and reduced side effects compared to existing agents.